Method for reducing serum lipoprotein(a) concentration

ABSTRACT

A method of reducing the serum Lp(a) concentration in a subject is disclosed. A suspension of small, unilamellar vesicles composed primarily of phospholipids, similar in nature to those of egg phosphatidylcholine, is administered parenterally to a subject having or at risk for developing a disease condition associated with an elevated serum Lp(a) concentration. In the method, liposomes are infused over an extended period of time of at least several weeks, until a significant drop in serum Lp(a) concentration is observed.

FIELD OF THE INVENTION

The present invention relates to a method for reducing the serumlipoprotein (a) (Lp(a)) concentration in a subject by intravenousadministration of a suspension of liposomes.

REFERENCES

Aroseleto, S., et al., LIPOSOME TECHNOLOGY (Gregoriadis, G., Ed.), pp.501-524, CRC Press, Boca Raton, Fla. (1993).

Barenholz, Y., et al., Biochemistry 16:2806 (1977).

Barenholz, Y., et al., LIPOSOME TECHNOLOGY (Gregoriadis, G., Ed), pp.524-607, CRC Press, Boca Raton, Fla. (1993).

Daida, H., et al., Am. J. Cardiol. 73(15):1037-1040 (1994).

Desmarais, R. L., et al., Circulation 91(5):1403-1409 (1995).

Groop, P. H., et al., Diabet. Med. 11(10):961-967 (1994).

Harrison, T. R., Ed., HARRISON'S PRINCIPLES OF INTERNAL MEDICINE,TWELFTH EDITION, pp. 1001-1015, McGraw Hill, Inc. (1991).

Kokoglu, E., et al., Cancer Biochem. Biophys., 14 (2): 133-136 (1994).

Levida, M., HANDBOOK OF NUTRITION IN THE AGED (Watson, R. R., Ed.), CRCPress, pp. 89-109 (1985).

Shinitsky, M., et al., J. Biol. Chem. 249:2652 (1974).

Szoka, F., et al., Ann. Rev. Biophys. Bioeng. 9:,467 (1980).

Takahashi, S., et al.. Ann. Rheum. Dis. 54(2):90-93 (1995).

Tenda, K., et al., Jpn. Circ. J. 57(8):789-795 (1993).

Yamamoto, K., et al., Metabolism 44(1) :4-7 (1995)

BACKGROUND OF THE INVENTION

There are several classes of globular, lipid-containing particles, knownas lipoproteins, that circulate in human blood and transport nonpolarlipids, primarily triglycerides and cholesteryl esters, through theplasma. Lipoproteins are classed according to the composition of thenonpolar lipids in the core of the particle and according to thecomposition of the apoproteins on the surface, and the density size andelectrophoretic mobility of the lipoprotein (Harrison, 1991).

Recent studies have shown various disease associations with above-normalor sub-normal levels of certain lipoproteins. It is known, for example,that serum Lp(a) is elevated in subjects with gout (Takahashi, et al.,1995), various types of cancer, such as breast cancer (Kokoglu, et al.,1994), hyperthyroidism (Yamamoto, et al., 1995), and in Type 1 diabeticswith early and established renal disease (Groop, et al., 1994). It hasalso been shown that there is a direct correlation between developmentof post-angioplasty restenosis and elevated serum Lp(a) concentrations(Tenda, et al., 1993).

SUMMARY OF THE INVENTION

In one aspect, the invention includes a method of reducing the Lp(a)concentration in a subject at risk for developing a disease conditionassociated with a chronic, elevated Lp(a) concentration, such as gout,breast cancer, hyperthyroidism, coronary heart disease or cerebralvascular disease. The method includes intravenously administering to thesubject a suspension of small unilamellar liposomes composed primarilyof phosphatidylcholine phospholipids having phase transitiontemperatures in the range between about -10° and 37° C., preferably atransition temperature of less than about 5° C., as exemplified by eggphosphatidylcholine (egg PC) which has a transition temperature of -5°C.

The liposomes in the composition are small unilamellar vesicles (SUV's),i.e., vesicles having sizes predominantly between 0.02 and 0.12 microns,and preferably 0.02-0.08 microns. The liposome suspension isadministered at a dose of between about 50-1,000 mg lipid/kg bodyweight. Multiple treatments may be given, e.g., at least once a week,over a several week period. Treatment is carried out until a desiredreduction in Lp(a) level is observed.

The treatment method may also be applied to a person having an elevatedLp(a) serum concentration and a disease, such as gout, breast cancer orhyperthyroidism, cerebral vascular disease, and coronary heart diseaseassociated with such elevated concentrations.

In another aspect, the invention provides a method of inhibitingrestenosis in a subject, following percutaneous transluminal coronaryangioplasty or surgical resection of vascular tissue. The methodincludes administering liposomes, as described above, until a reductionin serum Lp(a) concentration is observed.

In another aspect, the invention includes a method of achieving hairregrowth in a person suffering from male pattern baldness or alopecia,and a method of improving the periodontal condition in a person havingsymptoms of periodontal disease, such as gingivitis, tooth mobility orbone loss.

In both methods, a suspension of liposomes of the type described aboveis administered until a significant improvement in the condition isobserved.

These and other objects and features of the invention will be more fullyappreciated when the following detailed description of the invention isread in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1C are bar graphs showing serum phospholipid phosphorus levelsin three human subjects (FIG. 1A, FIG. 1B, FIG. 1C, respectively) for aperiod of 8 days, where continuous liposome infusion occurs in hours0-6.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

The term "elevated Lp(a) concentration", as used herein, refers to aserum Lp(a) concentration above 25 mg/dl.

The term "chronic elevated Lp(a) concentration", as used herein, refersto a concentration of Lp(a) that is on average elevated above normalaverage serum Lp(a) concentrations when measured at various times overthe course of a week. A normal average serum Lp(a) concentration isgenerally below 25 mg/dl.

The term "significant reduction in Lp(a) concentration", as used herein,refers to a reduction of at least 20%, preferably more than 40%, withrespect to the pretreatment Lp(a) concentration in a subject.

II. Preparation of Liposomes

The invention includes, in one aspect, administering to a human subjecta suspension of liposomes to reduce serum Lp(a) concentrations. Thesubject in need of such treatment is one having or at risk of developinga disease condition, such as those mentioned above, associated with achronic, elevated Lp(a) concentration.

In one preferred embodiment, described and used in the examples below,the liposomes are composed predominantly (more than 50 mole percent,preferably more than 80-90 mole percent) of phosphatidylcholine (PC)having a phase transition temperature less than about 37° C., preferablybetween about -10° to 24° C., e.g., 5° C. or lower.

One preferred vesicle composition includes egg PC, which containspredominantly 1-palmitoyl, 2-oleyl PC and 1-palmitoyl,2-linoleyl PC. Theliposomes may be composed entirely of the egg PC, which has a transitiontemperature of -5° C., or may contain other lipid components which (i)are not immunogenic, and (ii) do not contribute a significant portion,i.e., more than 25-50 mole percent, of lipids with high phase transitiontemperature. In the case where liposomes are composed of PC and one ormore other lipid components, the phospholipids making up the liposomewill have a collective phase transition temperature. In a preferredembodiment, the liposomes are composed of phospholipid, that is PC andone or more other lipid components, having a collective phase transitiontemperature of less than 5° C.

Additional components in the liposome composition may include negativelycharged lipids, such as phosphatidylglycerol (PG) or phosphatidylserine(PS). Of course, the mole percentage of these lipids should berelatively low with respect to PC. The liposomes may also includecholesterol or other sterols, in an amount preferably less than about 40mole percent.

Lipid protective agents, such as α-tocopherol, α-tocopherol acetate, orα-tocopherol succinate, may also be included in the lipids forming theliposomes, to protect the lipid components against free radical damage(Levida, 1985). Typically such agents are included at a mole percentagebetween about 0.05% and 2%. It is advantageous to add α-tocopherol tothe liposomes to maintain a balance between vitamin E andpolyunsaturated lipids in the liposomes.

A. Unsized Liposomes

A variety of methods for producing liposomes are available, and thesehave been extensively reviewed (Szoka, et al., 1980). In general thesemethods produce liposomes with heterogeneous sizes from about 0.02 to 10microns or greater. As will be discussed below, liposomes which arerelatively small and well defined in size are preferred for use in thepresent invention, hence a second processing step for reducing the sizeand size heterogeneity of liposomal suspensions will usually berequired.

In one preferred method for forming the initial liposome suspension, thevesicle-forming lipids are taken up in a suitable organic solventsystem, and dried in vacuo or under an inert gas to form a lipid film ina vessel. An aqueous suspension medium, such as a sterile salinesolution, is added to the film, and the vessel is agitated until thelipids have hydrated to completion, typically within 1-2 hours. Theamount of aqueous medium added is such as to produce a final liposomesuspension containing preferably between about 10 and 30 g lipid per 100ml media.

The lipids hydrate to form multilamellar vesicles (MLVs) whose sizesrange between about 0.5 microns to about 10 microns or larger. Ingeneral, the size distribution of MLVs can be shifted toward slightlysmaller sizes by hydrating the lipids under more vigorous shakingconditions. Example 1 describes the preparation of egg PC MLVs, prior totreating the MLVs with ultrasonic irradiation to reduce the liposomesizes.

The aqueous medium used in forming the liposomes may containwater-soluble agent(s) which enhance the stability of the liposomes uponstorage. A preferred stabilizing agent is an iron-specifictrihydroxamine chelating agent, such as desferrioxamine. The use of thiscompound in reducing lipid peroxidation and free radical damage indrug-containing liposomes has been reported in U.S. Pat. No. 4,797,285.Briefly, it was shown that the combination of a lipophilic free-radicalquencher, such as α-tocopherol, and the water-soluble chelator gavebetter protection against lipid peroxidation damage than did eitherprotective agent alone. The chelator is included in the aqueous mediumin molar excess of the amount of free iron in the medium. Typically, achelator concentration of between about 10-200 micromolar is sufficient.

B. Sizing Liposomes

The suspension of liposomes prepared as above is preferably treated toproduce a desired liposome size and size homogeneity.

The liposome suspension may be sized to achieve a distribution ofvesicles in a range less than about 0.12 microns and preferably lessthan about 0.08 microns.

Several techniques are available for reducing the sizes and sizeheterogeneity of liposomes, in a manner suitable for the presentinvention. Ultrasonic irradiation of a liposome suspension either bybath or probe sonication produces a progressive size reduction down toSUVs. A sonicating procedure used to produce SUVs is described inExample 1. Homogenization is another method which relies on shearingenergy to fragment large liposomes into smaller ones. In a typicalhomogenization procedure, MLVs are recirculated through a standardemulsion homogenizer until selected liposome sizes, typically less than0.1 microns, are observed.

Extrusion of liposomes through a small-pore polycarbonate membrane is aneffective method of reducing liposome size down to a relativelywell-defined size distribution. Sizes in a selected size range down to0.03 microns can be achieved (Example 2) by extrusion through apolycarbonate membrane having a selected pore size, e.g., in the poresize range 0.03-0.1 microns. Typically, the suspension is cycled throughthe membrane several times until the desired liposome size distributionis achieved. The liposomes may be extruded through successivelysmaller-pore membranes, to achieve a gradual reduction in liposome size.

The size-processed liposome suspension may be readily sterilized bypassage through a sterilizing membrane having a particle discriminationsize of about 0.2 microns, such as a conventional 0.22 micron depthmembrane filter. If desired, the liposome suspension can be lyophilizedin the presence of a cryoprotectant for storage and reconstitutedshortly before use. The final lipid concentration in the treatmentcomposition is preferably about 10% (w/w). A suspension of greater thanabout 15% lipid (w/w) may be too viscous for practical iv infusion, anda suspension concentration significantly less than 10% will require aproportionately longer infusion time.

III. Treatment Method and Results

This section describes various treatment methods which involveintravenous administration of liposomes of the type described above. Inthese methods, liposomes are preferably infused two or more times duringa period of at least two weeks, and at a dosing frequency of at leastone time per week. A preferred dosing frequency is one-two times perweek, although single-dose treatment is also contemplated. The dosingperiods, e.g., two weeks, may be interrupted by a wash-out period,typically of 1-4 weeks. The treatment, e.g., involving repeating dosingand wash-out periods, may continue over an extended period of severalmonths or more.

The amount of liposomes administered at each dose is between about10-1,000 mg lipid per kg of body weight, and preferably between about50-1,000 mg lipid per kg of body weight, although the dose may besubstantially less. Long term dosages are typically delivered at a rateof between about 0.001-1 g lipid per kg body weight per day. In apreferred embodiment, the liposome suspension is administered one timeper week, at a dose of about 200-500 mg lipid/kg body weight.

A typical dose for an 80 kg individual would be between about 10 and 80grams lipid, corresponding to between 100 and 800 ml of 10% liposome(w/w) suspension. Administration may be by iv (intravenous) injection,but is preferably done by iv drip (infusion) over a period of at leastabout 1-2 hour, to minimize discomfort at the site of administration.The liposomes may be suspended in sterile saline or in a nutritional ordrug-containing buffer or medium, such as a glucose/salt medium, tocombine liposome treatment with other parenteral therapy.

The method relies on the presence of administered liposomes in thebloodstream over an extended period following iv administration.Liposome levels in the blood following iv administration can bemonitored by measuring serum levels of phospholipids, e.g., phosphorus.FIGS. 1A-1C show phospholipid phosphorus levels measured in three humansubjects following a 6 hour iv infusion of liposomes. Liposomes,prepared as described in Example 1, were administered to each subject(FIG. 1A, 1B, and 1C, respectively) and serum phospholipid phosphorusand free cholesterol levels were monitored. Phospholipid phosphoruslevels were measured prior to liposome infusion (time=0) to establish abase level in each patient. The liposomes were infused continuously overa period of 6 hours and blood samples were taken midway through theinfusion period (time=3 hours) and at the end of infusion (time=6hours). Post-infusion, each subject was monitored for 192 hours (8 days)and blood samples were taken at various times.

As seen, the concentration of liposomes in the bloodstream is greatestat the end of the infusion period (time=6 hours), and phosphorus levelsgreater than normal levels were observed for at least 48 hours postinfusion, indicating the presence of exogenous circulatingphospholipids. The results indicate that with a liposome infusion timeof 6 hours, liposome dosing every two days would be effective inmaintaining elevated liposome levels during the dosing period. However,it is noted that the dosing schedule can be more infrequent, since it isnot necessary to maintain elevated liposome levels continuously in thetreatment method.

A. Reducing the Risk of Diseases Associated with Lb(a)

In one aspect the invention provides a method of reducing the serumLp(a) concentration in a person at risk for developing a diseasecondition associated with a chronic elevated serum Lp(a) concentration.Conditions associated with elevated Lp(a) concentrations include, forexample, gout, breast cancer and hyperthyroidism. Coronary heart diseaseand cerebral vascular disease are other conditions associated with highLp(a) levels.

A chronically elevated Lp(a) concentration refers to a serum Lp(a)concentration that is above about 25 mg/dl, typically representing anaverage of Lp(a) values, when measured several times over the course ofa week. Serum Lp(a) concentrations can be measured by a variety ofmethods, including enzyme-linked immunoabsorbent assay (ELISA), lateximmunoassay or immunoradiometric assay. A specific kit for determiningLp(a) concentration in a blood sample, Macra™, is available from TerumoDiagnostics (Elkin, Md.).

The treatment method, as applied to three male subjects, is described inExample 3. Briefly, each subject received a series of intravenousinfusions of liposomes prepared as described in Example 1, and at thedose schedule described in Example 3. At times just before liposomeinfusion (0 hours) and 24 hours after liposome infusion (24 hours),Lp(a) concentrations were measured, with the results shown in Table 1.Although several time points were not measured, it is clear from thedata that a significant reduction in Lp(a) was observed in all cases.For example, patient two, who had a relatively normal serum Lp(a) showeda drop from an initial concentration of 18 mg/dl to a concentration of14 mg/dl at the end of the treatment period, i.e., a 29% drop in serumLp(a) concentration. Subject 3 had an initial serum Lp(a) concentrationof 32 mg/dl, a concentration in the elevated Lp(a) range. At the end ofthe treatment period, the Lp(a) concentration was reduced to 18 mg/dl, a77% reduction.

                  TABLE 1                                                         ______________________________________                                                Dose     Time    Lp(a) (mg/dl)                                        Injection No.                                                                         (mg/kg)  (hours) Subject 1                                                                            Subject 2                                                                            Subject 3                              ______________________________________                                        1       200      0       --     18     32                                                      24      --     --     27                                     2       300      0       --     --     20                                                      24      --     --     18                                     3       300      0       --     3.8    --                                                      24      --     2.6    15                                     4       300      0       --     3      11                                                      24      --     3       9                                     5       300      0       37     16     24                                                      24      --     15     --                                     6       300      0       --     14     17                                                      24      --     --     10                                     7       300      0       25.6   --     --                                                      24      18.8   --     18                                     ______________________________________                                    

These results demonstrate the ability of the method to produce asignificant reduction in serum Lp(a) levels.

B. Treating Diseases Associated with Elevated Lp(a)

In another aspect, the invention includes a method of treating gout,breast cancer, or hyperthyroidism in a subject having one of theseconditions and an elevated serum Lp(a) concentration. Studies have shownthat serum Lp(a) concentrations are elevated in many subjects with gout(Takahashi, et al., 1995), various types of cancer, such as breastcancer (Kokoglu, et al., 1994), and hyperthyroidism (Yamamoto, et al.,1995). The purpose of this method is to treat the clinical disease bylowering Lp(a) levels, as one of the underlying factors contributing tothe disease.

Treatment, in accordance with the method of the invention, involvesfirst determining serum Lp(a) concentration in a person having one ofthe above clinical conditions. A patient having an elevated Lp(a) levelis then selected as a candidate for the liposome infusion method, asdescribed above, typically as an adjuvant to another treatment method,such as surgery, chemotherapy, or radiation therapy in the case ofbreast cancer. Treatment is maintained until a significant reduction inLp(a) is observed and preferably throughout the treatment period for theclinical disease.

C. Treatment of Restenosis

Restenosis occurs in approximately 20-30 percent of patients followingpercutaneous transluminal coronary angioplasty. Restenosis can alsooccur in patients following surgical resectioning of vascular tissue. Inthis procedure, a region of stenosis in a vessel is removed and thevessel is sutured closed. Restenosis in each case is apparently theresult of excessive local myointimal hyperplasia, brought about byplatelet aggregation to the freshly dilated or sutured vessel surface(Harrison, 1991).

Recent studies have shown that high serum Lp(a) concentrations areassociated with an increased incidence of restenosis after balloonangioplasty (Daida, et al., 1994; Desmarais, et al., 1995; Tenda, etal., 1993). In one study, patients with a serum Lp(a) level of 38 mg/dlhad a significantly higher level of restenosis than patients with aserum level of 19.9 mg/dl (Tenda, et al., 1993).

The present invention includes a method a reducing the extent ofrestenosis following procedures such as balloon angioplasty or surgicalresectioning of vascular tissue. Typically in the method, a personundergoing such a procedure that can lead to restenosis is given one ormore pretreatment infusions of liposomes, particularly where existingLp(a) levels are elevated, to achieve a reduction in such levels.Following the procedure, the patient is again monitored for Lp(a) serumconcentrations, and given further liposome infusions if necessary tomaintain or achieve low Lp(a) levels, e.g., 20 mg/dl or lower. Thetreatment may be discontinued after a period of several weeks or morewhen the risk of restenosis has passed.

D. Periodontal Treatment

The invention also includes a method of improving the periodontalcondition of a person suffering from periodontal disease, as evidenced,for example, by gingivitis, bone resorption, pocket formation or toothmobility.

Liposomes were administered, in accordance with the method of theinvention, to a male subject having a history of periodontal disease, asevidenced by severe bleeding gingiva, Class II and III mobility andpocket depths between 4-8 mm. Liposomes were infused according to thedosing schedule described in Example 3, and following treatment asignificant improvement in the patient's dental health was observed.Periodontal pocket depths decreased to between 2-4 m/n, except aroundtwo teeth where the pocket depth remained at 8 mm. Periodontal scalingand root planing indicated that very little bleeding was present, andteeth mobility was reduced to Class I.

Treatment by liposome administration may be continued until a desiredimprovement in gum condition is achieved.

E. Hair Regrowth

In another aspect, the invention includes a method of improving hairregrowth in a person having alopecia or male pattern baldness.

An elderly male subject with scalp hair loss was treated with liposomes,administered according to the dosing schedule described in Example 3.The subject noticed a significant improvement in hair regrowth afterliposome treatment.

The following examples illustrate various methods for preparing liposomecompositions and using the compositions in the treatment method of theinvention. The examples are intended to illustrate, but in no way limit,the scope of the invention.

MATERIALS

Egg phosphatidylcholine (egg PC) recovered from egg yolk was preparedaccording to known methods (Shinitsky, et al., 1974). High purity egg PCmay also be purchased from Avanti Polar Lipids (Alabaster, Ala.) orLipoid KG (Ludwigshafen, Germany). The egg PC was determined to begreater than 99% pure, based on thin layer chromatography (TLC)analysis. The egg PC fatty acid composition was similar to the reportedcomposition. The main PC,s of the preparation included1-palmitoyl,2-oleyl PC and 1-palmitoyl,2-linoleyl PC. Thin-layerchromatography plates, 0.25 silica gel HR and 0.024 silica gel, wereobtained from Merck (Darmstadt, Germany) and Analtech (Newark, Del.)respectively.

EXAMPLE 1 Preparation of Small Unilamellar Vesicles: Sonication

Egg PC dissolved in chloroform was placed in a 100 ml vessel and driedto a thin film under nitrogen. Sterile saline was added to the lipidfilm to a final concentration of about 100 mg/ml, and the lipid film washydrated with swirling. The resulting multilamellar vesicle (MLV)suspension was then bath sonicated for 1 hour using a Heat SystemSonicator, Model 375W, at a power setting of 40-50% full value. Thetemperature of the suspension was maintained at about 4° C. undernitrogen during sonication. The sonicated suspension was separated fromlarge vesicles by ultracentrifugation at 100,000 g for 1 hour(Barenholz, et al., 1977). The suspension of SUVs, having aconcentration of about 100 mg/ml, was filter sterilized.

EXAMPLE 2 Preparation of Small Unilamellar Vesicles: Extrusion

Homogeneous small unilamellar vesicles of egg PC with an averagediameter of 39±8 nm, in 0.15M NaCl were prepared by extrusion usingserial filtration through polycarbonate filters in a GH 76-400 pressurecell (Nucleopore, Pleasanton, Calif.) (Amselem, et al., 1993). Liposomalsize was determined using a Coulter model N4 sub-micron particleanalyzer equipped with a size distribution processor analyzer(Barenholz, et al., 1993). The final extrusion step was through a 0.05micrometer pore polycarbonate filter. Egg PC SUV's were sterilized byfiltration through sterile 0.22 micrometer Millipore filters.

EXAMPLE 3 Effect of Egg PC SUV Treatment On Lp(a) Serum Concentration

Liposomes prepared as described in Example 1 were administered to threemale subjects, identified herein as subjects 1, 2 and 3, having ages 40,54 and 64 years, respectively.

At the start of treatment, each subject was given a 250 ml intravenousinfusion of 0.9% saline followed by intravenous infusion of SUVliposomes at a dose of 200 mg lipids/kg body weight. Once a week for thenext three weeks, each subject received by intravenous infusion 300mg/kg of liposomes. After a 3-4 week washout period, each subjectreceived 300 mg/kg of liposomes one time per week for three weeks. Table1 summarizes the treatment regimen and shows the serum Lp(a)concentration of each subject during the course of treatment.

While various embodiments of the invention have been described herein,it will be apparent that various modifications can be made withoutdeparting from the intended scope of the invention.

It is claimed:
 1. A method of inhibiting restenosis in a subject following percutaneous transluminal coronary angioplasty or surgical resection of vascular tissue, comprisingdetermining a pretreatment serum Lp(a) concentration of the subject, intravenously administering to the subject a suspension of small unilammellar liposomes composed primarily of phosphatidylcholines having phase transition temperatures in the range between about -10° and 37° C., and repeating said administering over a period of at least about two weeks, and in an amount effective to produce a reduction in serum Lp(a) concentration in the subject of at least 20% relative to the pretreatment serum Lp(a) concentration of the subject.
 2. The method of claim 1, in which the subject is determined to have an elevated pretreatment serum Lp(a) concentration.
 3. The method of claim 2, wherein said liposomes range in size from about 0.02 to about 0.12 microns.
 4. The method of claim 2, wherein said phosphatidylcholines are egg phosphatidylcholines.
 5. The method of claim 2, wherein said phosphatidylcholines have phase transition temperatures less than about 5° C.
 6. The method of claim 2, wherein said liposome suspension is administered at least one time per week and at a dose in the range of about 50-1,000 mg lipid/kg body weight.
 7. The method of claim 2, wherein the method is practiced on the subject following percutaneous transluminal coronary angioplasty.
 8. The method of claim 2, wherein the method is practiced on the subject following surgical resection of vascular tissue.
 9. A method of inhibiting restenosis in a subject having an elevated pretreatment serum Lp(a) concentration following percutaneous transluminal coronary angioplasty or surgical reaction of vascular tissue, comprisingintravenously administering to the subject a suspension of small unilamellar liposomes consisting essentially of phosphatidylcholines having phase transition temperatures in the range between about -10° and 37° C., and repeating the administering of the liposomes over a period of at least about two weeks at least one time per week at a dose in the range of about 50-1,000 mg lipid/kg body weight of the subject in a manner effective to produce a reduction in serum Lp(a) concentration in the subject of at least 20% relative to the protreatment serum Lp(a) concentration of the subject.
 10. The method of claim 9, wherein said liposomes range in size from about 0.02 to about 0.12 microns.
 11. The method of claim 10, wherein the said phosphatidylcholines are egg phosphatidylcholines.
 12. The method of claim 11, wherein said phosphatidylcholines have phase transition temperatures less than about 5° C.
 13. The method of claim 12, wherein the method is practiced on the subject following percutaneous transluminal coronary angioplasty.
 14. The method of claim 12, wherein the method is practiced on the subject following surgical resection of vascular tissue. 